We characterize a novel pathogenic variant in COL11A1, raising a new diagnostic consideration for patients presenting with congenital hypotonia and axial weakness.

Collagens are triple helical proteins present in the extracellular matrix (ECM) and at the cell–ECM interface. Type XI collagen is a minor fibrillar collagen that is broadly expressed, including in articular cartilage, tendons, trabecular bone, and skeletal muscle. COL11A1 is a large complex gene of 68 exons, and the COL11A1 protein forms a heterotrimer with COL11A2 and COL2A1 to assemble type XI collagen. Pathogenic variants in COL11A1 are associated with type II Stickler syndrome and Marshall syndrome, autosomal dominant disorders presenting with varying degrees of craniofacial dysmorphology, ocular abnormalities, hearing loss, and skeletal anomalies. Muscle involvement has not been previously described.

We describe a child with congenital hypotonia, delayed motor development and persistent mild axial weakness, who along with his mother, exhibits skeletal anomalies, joint hyperlaxity, juvenile cataracts, and muscle involvement on US imaging. Family history was significant for an affected mother. Whole exome sequencing analysis identified a splice-donor–site single nucleotide variant in COL11A1 (c.3276+5G>A) that co-segregates with the phenotype.

Functional studies were completed to determine the effects of this variant. RNA was extracted from cultured dermal fibroblasts from the affected mother, and custom primers were designed to cover exons 41-43.

Endpoint PCR showed that the splice site variant results in an in-frame skipping of the 108-bp exon42 and deletes amino acids 1056-1092 from the triple-helical domain of the alpha1 (XI) collagen polypeptide. Loss of the encoded residues in the triple-helical region is expected to act in a dominant negative manner and disrupt normal protein folding and function.

This case illustrates the phenotypic variability of COL11A1-related disorders, highlighting the potential for muscle involvement, adding collagen XI to disorders of the "myomatrix", which include collagenopathies with skeletal muscle involvement.